PT  - JOURNAL ARTICLE
AU  - Angel C.Y. Mak
AU  - Marquitta J. White
AU  - Zachary A. Szpiech
AU  - Walter L. Eckalbar
AU  - Sam S. Oh
AU  - Maria Pino-Yanes
AU  - Donglei Hu
AU  - Pagé Goddard
AU  - Scott Huntsman
AU  - Joshua Galanter
AU  - Dara G. Torgerson
AU  - Ann Chen Wu
AU  - Blanca E. Himes
AU  - Soren Germer
AU  - Julia M. Vogel
AU  - Karen L. Bunting
AU  - Celeste Eng
AU  - Sandra Salazar
AU  - Kevin L. Keys
AU  - Jennifer Liberto
AU  - Thomas J. Nuckton
AU  - Thomas A. Nguyen
AU  - Pui-Yan Kwok
AU  - Albert M. Levin
AU  - Juan C. Celedón
AU  - Erick Forno
AU  - Hakon Hakonarson
AU  - Patrick M. Sleiman
AU  - Amber Dahlin
AU  - Kelan G. Tantisira
AU  - Scott T. Weiss
AU  - Denise Serebrisky
AU  - Emerita Brigino-Buenaventura
AU  - Harold J. Farber
AU  - Kelley Meade
AU  - Michael A. Lenoir
AU  - Pedro C. Avila
AU  - Saunak Sen
AU  - Shannon M. Thyne
AU  - William Rodriguez-Cintron
AU  - Cheryl A. Winkler
AU  - Andrés Moreno-Estrada
AU  - Karla Sandoval
AU  - Jose R. Rodriguez-Santana
AU  - Rajesh Kumar
AU  - L. Keoki Williams
AU  - Nadav Ahituv
AU  - Elad Ziv
AU  - Max A. Seibold
AU  - Robert B. Darnell
AU  - Noah Zaitlen
AU  - Ryan D. Hernandez
AU  - Esteban G. Burchard
ED  - ,
TI  - Whole genome sequencing of pharmacogenetic drug response in racially and ethnically diverse children with asthma
AID  - 10.1101/128116
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 128116
4099  - http://biorxiv.org/content/early/2017/09/15/128116.short
4100  - http://biorxiv.org/content/early/2017/09/15/128116.full
AB  - Asthma is the most common chronic disease of children, with significant racial/ethnic differences in prevalence, morbidity, mortality and therapeutic response. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. We performed the largest whole genome sequencing (WGS) pharmacogenetics study to date using data from 1,441 minority children with asthma who had extremely high or low bronchodilator drug response (BDR). We identified population-specific and shared pharmacogenetic variants associated with BDR, including genome-wide significant (p < 3.53 x 10-7) and suggestive (p < 7.06 x 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling pathways (ADAMTS3 and COX18). Functional analyses centered on NFKB1 revealed potential regulatory function of our BDR-associated SNPs in bronchial smooth muscle cells. Specifically, these variants are in linkage disequilibrium with SNPs in a functionally active enhancer, and are also expression quantitative trait loci (eQTL) for a neighboring gene, SLC39A8. Given the lack of other asthma study populations with WGS data on minority children, replication of our rare variant associations is infeasible. We attempted to replicate our common variant findings in five independent studies with GWAS data. The age-specific associations previously found in asthma and asthma-related traits suggest that the over-representation of adults in our replication populations may have contributed to our lack of statistical replication, despite the functional relevance of the NFKB1 variants demonstrated by our functional assays. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.AUTHOR SUMMARY Asthma is the most common chronic disease among children. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. In the U.S., asthma prevalence is the highest among Puerto Ricans, intermediate among African Americans and lowest in Whites and Mexicans. Asthma disparities extend to mortality, which is four- to five-fold higher in Puerto Ricans and African Americans compared to Mexicans [1]. Puerto Ricans and African Americans, the populations with the highest asthma prevalence and death rate, also have the lowest albuterol bronchodilator drug response (BDR). We conducted the largest pharmacogenetic study using whole genome sequencing data from 1,441 minority children with asthma who had extremely high or low albuterol bronchodilator drug response. We identified population-specific and shared pharmacogenetic variants associated with BDR. Our findings help inform the direction of future development of asthma medications and our study advances the foundation of precision medicine for at-risk, yet understudied, racially/ethnically diverse populations.